ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage

TLDR

DNA damage responses are orchestrated by kinases such as ATM and ATR, yet the full physiological scope of the DDR remains largely undefined. The authors conducted a large‑scale proteomic screen of ATM/ATR‑phosphorylated proteins, uncovering over 900 regulated sites across more than 700 proteins. The dataset is enriched for DDR proteins, revealing extensive interconnections and novel protein modules that broaden the known DDR landscape.

Abstract

Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this data set indicated that this list is highly enriched for proteins involved in the DDR. This set of proteins is highly interconnected, and we identified a large number of protein modules and networks not previously linked to the DDR. This database paints a much broader landscape for the DDR than was previously appreciated and opens new avenues of investigation into the responses to DNA damage in mammals.